The Helix-Loop-Helix (HLH) family of Eukaryotic Transcription Factors is characterized by a conserved DNA-binding domain which is both necessary and sufficient for specific dimerization and DNA-binding. Members of the family are widespread, and play critical roles in the regulation of metabolism, development and cell proliferation in eukaryotes ranging from yeast to man. In order to gain a detailed and predictive understanding of the way in which these proteins recognize DNA and exert their biological functions, we have undertaken a concerted biochemical and x-ray crystallographic investigation of a number of different HLH proteins. To date, we have determined the crystal structures of the human transcription factor USF and the mammalian oncoprotein MAX, both bound to their target DNA sequence. Detailed biochemical investigation has shown that DNA binding by these proteins proceeds through an induced fit mechanism where more than forty amino acid residues change conformation concomitant with high-affinity binding, further work is in progress on a number of additional homo- and hetero-dimeric HLH proteins